Association between lipocalin-2 and mild cognitive impairment or dementia: A systematic review and meta-analysis of population-based evidence.

BACKGROUND: The associations between lipocalin-2 (LCN2) with mild cognitive impairment (MCI) and dementia have gained growing interest. However, population-based studies have yielded inconsistent findings. Therefore, we conducted this essential systematic review and meta-analysis to analyze and summarize the existing population-based evidence. METHODS: PubMed, EMBASE, and Web of Science were systematically searched until Mar 18, 2022. Meta-analysis was performed to generate the standard mean difference (SMD) of peripheral blood and cerebrospinal fluid (CSF) LCN2. A qualitative review was performed to summarize the evidence from postmortem brain tissue studies. RESULTS: In peripheral blood, the overall pooled results showed no significant difference in LCN2 across Alzheimer's disease (AD), MCI and control groups. Further subgroup analysis revealed higher serum LCN2 levels in AD compared to controls (SMD =1.28 [0.44;2.13], p = 0.003), while the difference remained insignificant in plasma (SMD =0.04 [-0.82;0.90], p = 0.931). Besides, peripheral blood LCN2 were higher in AD when age difference between AD and controls ≥ 4 years (SMD =1.21 [0.37;2.06], p = 0.005). In CSF, no differences were found in LCN2 across groups of AD, MCI and controls. However, CSF LCN2 was higher in vascular dementia (VaD) compared to controls (SMD =1.02 [0.17;1.87], p = 0.018), as well as compared to AD (SMD =1.19 [0.58;1.80], p < 0.001). Qualitative analysis supported that LCN2 was increased in the brain tissue of AD-related areas, especially in astrocytes and microglia; while LCN2 increased in infarct-related brain areas and over-expressed in astrocytes and macrophages in mixed dementia (MD). CONCLUSION: The difference in peripheral blood LCN2 between AD and controls may be affected by the type of biofluid and age. No differences were found in CSF LCN2 across AD, MCI and controls groups. In contrast, CSF LCN2 was elevated in VaD patients. Moreover, LCN2 was increased in AD-related brain areas and cells in AD, while in infarcts-related brain areas and cells in MD.

Limitations in activities of daily living increase the risk of stroke in older Chinese adults: a population-based longitudinal study.

It remains unclear whether limitations in activities of daily living (ADL) increase the risk of stroke in older Chinese adults. This longitudinal study used data from the Chinese Longitudinal Healthy Longevity Survey to investigate the effects of limitations in ADL on the incidence of stroke in older adults. Between 2002 and 2011, 46,728 participants from 22 provinces in China were included in this study. Of participants, 11,241 developed limitations in ADL at baseline. A 3-year follow-up was performed to determine the incidence of stroke. During the 3-year follow-up, 929 participants (8.26%) and 2434 participants (6.86%) experienced stroke in the ADL limitations group and non-ADL limitations group, respectively. Logistic regression was used to analyze the effect of ADL limitations on the risk of stroke. The results showed that after adjusting for the confounding factors gender, age, weight, hypertension, diabetes, heart disease, natural teeth, hearing impairment, visual impairment, smoking, alcohol abuse, exercise, ethnicity, literacy, residential area, and poverty, the ADL limitations group had a 77% higher risk of developing stroke than the non-ADL limitations group. After propensity score matching, the ADL limitations group still had a 33% higher risk of developing stroke than the non-ADL limitations group (OR = 1.326, 95% CI: 1.174-1.497). These findings suggest that limitations in ADL are a stroke risk factor.

Outer membrane vesicles enhance tau phosphorylation and contribute to cognitive impairment.

Outer membrane vesicles (OMVs) are nanosized vesicles produced by the gut microbiota (GM). The GM is well-known to be involved in the pathological process of Alzheimer's disease (AD). However, the mechanism of OMVs is not clear. In the present study, we demonstrated the involvement of OMVs in the development of cognitive (learning and memory) dysfunction induced by blood-brain barrier (BBB) disruption. More important, further study showed that OMVs induced tau phosphorylation by activating glycogen synthase kinase 3ß (GSK-3ß) in the hippocampus. OMVs activated astrocytes and microglia, increased secretion of inflammatory cytokines (nuclear factor κB, interleukin-1ß, and tumour necrosis factor-α) in the hippocampus. Therefore, OMVs increase the permeability of the BBB and promote the activation of astrocytes and microglia, inducing an inflammatory response and tau hyperphosphorylation by activating the GSK-3ß pathway and finally leading to cognitive impairment.